tbuckley/cabot-search huggingface dataset:
Abstract 1171: Genotoxic preventive potential of ethanol leaves extract of <i>Annona muricata</i> on N-Nitroso-N-ethylurea pro-leukaemia carcinogen in mice by bone marrow micronucleus assay
Authors: Olufemi Emmanuel Akanni, Eunice Oluwaseyi Bamisaye, Sunday Anthony Fashina, Fatai Adesina Abdulraheem, Solomon Olufemi Fadiora
Journal: Cancer Research (2022)

Abstract Background: Genotoxicity which is an important indicator of DNA damage, repair and cell rejuvenation has been a predisposing factor to cancer development evidenced by bone marrow suppression in leukemia and studies have proven the effect of several agents inclusive of natural products to induce, prevent and treat genotoxicity through experimental models and clinical trials. Aim:The genotoxic preventive potential of Annona muricata ethanol leaves extract on N-nitroso-N-ethylurea (NEU) pro-leukemia carcinogen in mice model using micronuclei formation in bone marrow was assessed. Materials and Methods: 48 mice weighing 18-24g were randomly divided into six groups of eight mice each comprising of the; mice intravenously administered 20mg/kg of NEU 48 hourly 3 times (A); 80mg/kg of NEU 48 hourly 3 times (B); negative control fed with feed and water only (C); 0.2ml (0.1g/ml) ethanolic leaves extract of Annona muricata for 3 weeks prior to administration of low dose of NEU (D); 0.2ml (0.1g/ml) ethanolic extract of Annona muricata for 3 weeks prior to administration of high dose of NEU (E); and Annona muricata (ethanolic leaves extract) and commercial diet for adverse/toxicity group (F). After six weeks of last exposure, animals were ethically sacrificed, bone marrow harvested, smeared, stained using MayGrumwald and number of micronucleus polychromatic erythrocyte (MNPCEs) were determined microscopically.Result: Groups exposed to various dosage of the NEU yielded significantly increased MNPCEs with group B producing higher MNPCEs than A. The groups treated with extract displayed a significant reduction in the MNPCEs despite the prior exposure concentrations of NEU. The adverse group displayed no difference in MNPCEs when compared with the negative control (Table 1). Conclusion: The extract displayed profound capacity to prevent genotoxicity thereby alleviating leukemia condition and it is well tolerated. Week Number Groups (Mean±Standard deviation of MNPCE) A B C D E F 2 14.13±0.56 50.45±2.31 4.52±0.34 6.15±0.49 17.11±1.11 4.53±0.45 3 15.01±0.18 53.77±1.95 4.61±0.67 7.85±0.98 20.34±2.34 4.62±0.23 4 16.11±0.22 56.95±2.01 4.91±0.88 8.01±1.01 25.11±1.67 5.63±0.45 5 19.64±1.68 68.23±1.56 4.82±0.75 10.07±0.67 30.54±2.34 5.92±0.67 Citation Format: Olufemi Emmanuel Akanni, Eunice Oluwaseyi Bamisaye, Sunday Anthony Fashina, Fatai Adesina Abdulraheem, Solomon Olufemi Fadiora. Genotoxic preventive potential of ethanol leaves extract of Annona muricata on N-Nitroso-N-ethylurea pro-leukaemia carcinogen in mice by bone marrow micronucleus assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1171.
Abstract 5553: Anti-CD19-CD22 antibody drug conjugate to reduce tumor recurrence in B-cell hematologic cancers
Authors: Liang Du, Tingting Wan, Yi Jin, Jijun Yuan
Journal: Cancer Research (2022)

Abstract With 1,279,000 new cases in 2020 and high incidence of relapse, hematologic cancers present significant opportunity for drug development. B-cell caners arise from various developmental stages of the B lymphocyte, and occur in several forms, including leukemia, lymphoma, and multiple myeloma. CD19 and CD22 are validated targets for B cell cancers, each with multiple drugs approved. However, single targeting therapies showed a poor median response likely due to loss of antigen expression upon treatment stress. CD19&amp;CD22 dual targeting antibody drug conjugate can be a powerful killer of B-cell cancers, with more targeted patient populations due to the high expression of CD19, and good anti-tumor efficacy due to the high internalizing ability of CD22.To this end, we developed 7E11-13G9, which is a bispecific antibody designed for antibody-drug-conjugate for a larger market of B-cell hematological cancers.By the strong CD19 binding arm of 7E11 and the efficient CD22-mediated internalizing arm of 13G9, 7E11-13G9 BsAb kills more tumor cells with high potency and efficacy. In tumor cell killing assay, bispecific 7E11-13G9 showed significantly better anti-tumor efficacy than any of the benchmark antibodies, and even better than the combination of the anti-CD19 benchmark Loncastuximab with the anti-CD22 benchmark Inotuzumab. Significantly better anti-tumor effect and delayed tumor recurrence of CD19-CD22 bispecific compared with single target was demonstrated in Nalm6 acute lymphocyte leukemia model. 7E11-13G9 BsAb is stable and has good productivity in transient expression. Proof of concept study of antibody drug conjugate based on 7E11-13G9 was prepared, and showed great anti-tumor efficacy both in vitro and in vivo. Citation Format: Liang Du, Tingting Wan, Yi Jin, Jijun Yuan. Anti-CD19-CD22 antibody drug conjugate to reduce tumor recurrence in B-cell hematologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5553.
Abstract 1740: Determining the intracellular fate of ligand-conjugated therapeutics using nanogold labeling
Authors: Ikjot S. Sohal, Ahmed M. Abdelaal, Andrea L. Kasinski
Journal: Cancer Research (2022)

Abstract Recent developments in ligand-conjugated RNAi therapeutics have led to improved stability of RNAi molecules, reducing effective therapeutic dose, and avoiding delivery vehicle-associated toxicity. However, as our group has shown in previous studies with FolamiR (Folate-conjugated miR-34a), endosomal entrapment of the therapeutic molecule is a rate-limiting factor in RNAi activity. To improve endosomal release of ligand-conjugates, several approaches are being explored such as incorporation of endosomal escape agents (nigericin), chemical modification to enhance stability of miRNA/siRNA within the acidic compartments, and modification of ligand-receptor interaction to enable adequate release from the receptor upon internalization. Current fluorescent microscopy techniques are only able to approximately estimate the cellular fate of FolamiR without providing enough resolution to determine the endosomal stage, receptor disengagement and other dynamics involved in the endosomal entrapment/release of FolamiR. To overcome this, we developed Folate-conjugated nanogold construct (FolaGold) that mimics FolamiR molecule. The nanogold in FolaGold is used as a proxy for miR-34a and electron microscopy can be performed to pinpoint the cellular fate of nanogold including receptor disengagement process, the endosomal stage as well as cytosolic enrichment at the nanometer resolution. In this study, FolaGold is validated to bind to folate receptor in a competition assay and is confirmed to be present in specific endosomal compartments in MB231 cells, unlike unconjugated nanogold. We further plan to use FolaGold to determine changes in intracellular fate of nanogold upon incorporation of endosomal escape agents (nigericin) and modification of ligand-receptor interaction by using a lower affinity binding ligand that facilitates ligand-receptor disengagement following internalization. While we are using nanogold labeling to determine the intracellular fate of ligand-conjugated RNAi therapeutics, the labeling can also help improve our understanding of endosomal release dynamics and activity of other ligand-conjugate based therapeutics. Citation Format: Ikjot S. Sohal, Ahmed M. Abdelaal, Andrea L. Kasinski. Determining the intracellular fate of ligand-conjugated therapeutics using nanogold labeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1740.
Abstract 1094: <i>SMARCA4</i>-mediated chromatin remodeling regulates osimertinib resistance in <i>EGFR</i>-mutant lung adenocarcinoma
Authors: Fernando J. de Miguel, Wesley L. Cai, Mary Ann Melnick, Camila Robles-Oteiza, Anna Wurtz, Maria I. Toki, David L. Rimm, Robert Homer, Don X. Nguyen, Katerina A. Politi
Journal: Cancer Research (2022)

Abstract Targeted therapies have transformed the clinical management of many types of tumors, including EGFR-mutant lung adenocarcinomas. Although these treatments are highly beneficial for patient survival, acquired resistance almost inevitably occurs limiting cures with these agents. The tyrosine-kinase inhibitor (TKI) osimertinib is approved for the first-line treatment of EGFR-mutant lung tumors and leads to increased progression-free and overall survival compared to earlier generations of TKIs. However, acquired resistance to osimertinib frequently occurs and is mostly due to off-target mechanisms, many of which are not well-understood. Therefore, it is critical to understand the molecular processes behind these mechanisms of resistance. We generated osimertinib resistant cell lines and patient-derived models to identify and study novel mechanisms of osimertinib resistance. We found that, in some osimertinib resistant tumors, SMARCA4 is stabilized upon osimertinib treatment and knock-down of SMARCA4 re-sensitizes the resistant cells to osimertinib and globally alters their chromatin profile. ATAC-Seq and RNA-Seq studies revealed that SMARCA4 alters chromatin accessibility in resistant tumors to maintain the transcriptional activity of genes involved in cell proliferation. Furthermore, SMARCA4 enables access to NRF2 binding sites enhancing an antioxidant response necessary for cells to tolerate the increase in reactive oxygen species and oxidative stress created by osimertinib. These processes converge and lead to an increase in the amount of DNA damage that is repaired by ATR. Indeed, we found that these osimertinib resistant tumors are vulnerable to ATR inhibition. In summary, we have identified a new epigenetic mechanism of resistance to osimertinib driven by SMARCA4 that generates a vulnerability to ATR inhibition, offering new approaches to target TKI-resistant tumors. Citation Format: Fernando J. de Miguel, Wesley L. Cai, Mary Ann Melnick, Camila Robles-Oteiza, Anna Wurtz, Maria I. Toki, David L. Rimm, Robert Homer, Don X. Nguyen, Katerina A. Politi. SMARCA4-mediated chromatin remodeling regulates osimertinib resistance in EGFR-mutant lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1094.
Abstract 1886: Targeting oral squamous cell carcinoma tumor microenvironment through simultaneous modulation of pattern recognition receptors and angiogenic factors using a synthetic polymer-based drug
Authors: Won Yong Lee, Frida Ponthan, Stephen T. Sonis
Journal: Cancer Research (2022)

Abstract Squamous cell carcinomas (SCCs) are the dominant form of cancers of the upper aerodigestive tract. Main risk factors are smoking and human papilloma virus (HPV) infection. Despite the HPV vaccination efforts, the number of oropharyngeal cancers (OSCCs) has been steadily increasing especially in males. Standard of care primarily focuses on the surgical removal of cancerous tissues followed by chemoradiation therapy. However, the recurrence rate of OSCCs remains fairly high as the tumor frequently develops therapy resistance and more effective therapeutic regimens are needed. The chronic inflammatory state yet paradoxical immunosuppressive tumor microenvironment has been regarded as a cause of therapy resistance and suggested as a potential therapeutic target. Pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) contribute to pro-inflammatory tissue responses. TLR2 present in the OSCC tumor appears to play important roles in regulating immune responses and promoting pro-inflammatory tumor microenvironment. GM-1111 is a synthetic glycosaminoglycan-based anti-inflammatory molecule that potently inhibits PRRs such as TLR2 and NLRP3 inflammasome. In addition, GM-1111 inhibits multiple angiogenic molecules - CXCL12, VEGF, and FGF2. We hypothesized that GM-1111 might be able to reduce OSCC tumor growth by simultaneously disrupting pro-inflammatory as well as angiogenic signaling. To test this hypothesis, male CD1 nude mice bearing FaDu cell tumor in the back were treated with either (1) vehicle, (2) GM-1111 (30 mg/kg, q.d., s.c.), (3) vehicle with irradiation (2 Gy/day x 5 days), or (4) GM-1111 with irradiation 17 days. Established tumors grew in two phases from slow for the initial 7 days to fast growths during the remaining days. Irradiation- or drug-induced tumor regression was observable about 5 days after the last radiation therapy (day 10). Compared to the vehicle only (1) treatment group, GM-1111 treated animals (groups 1 vs. 2: p = 0.0032; groups 1 vs. 3: p &amp;lt; 0.0001; groups 1 vs. 4: p &amp;lt; 0.0001) demonstrated significantly reduced tumor growth. These results suggest that GM-1111 has a potential to reduce OSCC and further confirm our previous orthotopic human tongue SCC-25 cell xenograft study data. Citation Format: Won Yong Lee, Frida Ponthan, Stephen T. Sonis. Targeting oral squamous cell carcinoma tumor microenvironment through simultaneous modulation of pattern recognition receptors and angiogenic factors using a synthetic polymer-based drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1886.
Abstract 5660: Anti-proliferation effect of polo-like kinase-4 inhibitor in ovarian cancer via AKT/mTOR/p70S6K pathway
Authors: Ka Yu Tse, Wai Sun Chan, Moxil Xuetang Mo, Horace Hok Yeung Lee, Philip Pun Ching Ip, Tak Wah Mak
Journal: Cancer Research (2022)

Abstract Background: Chromosomal instability is a hallmark in epithelial ovarian cancer. Polo-like kinases (PLK) play a vital role in cell cycle regulation. In particular, PLK4 is crucial in centriole duplication. PLK4 overexpression causes defect in cytokinesis, which in turn leads to aneuploidy and mitosis catastrophe. Previous studies showed that PLK4 inhibitors are effective against cell growth in different cancers like breast cancer and lung cancer. We hypothesize that the AKT/mTOR and p70S6K pathway is involved in this mechanism. Methods: The importance of cell proliferation of PLK4 was assessed by its inhibition in ovarian cancer cell lines and patient-derived organoids by CFI-400945. RNA sequencing was performed. The effects of PLK4 inhibition on the AKT/mTOR and p70S6K pathway was demonstrated by qPCR and western blot. Correlation of the mRNA expression level with the IC50 of CFI-400945 in ovarian cancer cell lines. Results: PLK4 inhibition led to reduced cell proliferation in ovarian cancer cells based on XTT and colony formation assays. The anti-proliferative effect was further confirmed in 12 patient-derived organoids using ATP bioluminescent assay. RNA sequencing showed that PLK4 inhibition led to downregulation of the AKT/mTOR/p70S6K pathway. It was found that the most sensitive cell line had the highest mRNA expression of mTOR and p70S6K, while those less sensitive had lower mTOR and p70S6K mRNA expression. Treatment with CFI-400945 showed a reduction of total and phosphorylated forms of AKT, mTOR and p70S6K in a dose-dependent level. Combined treatment with metformin, a drug that had mTOR inhibition effect, showed a synergistic effect in one ovarian cancer cell line. Conclusion: PLK4 inhibition caused reduced cell proliferation in in vitro and ex vivo assays, and this was accompanied by a downregulation of the AKT/mTOR/p70S6K pathway. This suggested that this pathway might be one of the downstream effector pathways of PLK4. Citation Format: Ka Yu Tse, Wai Sun Chan, Moxil Xuetang Mo, Horace Hok Yeung Lee, Philip Pun Ching Ip, Tak Wah Mak. Anti-proliferation effect of polo-like kinase-4 inhibitor in ovarian cancer via AKT/mTOR/p70S6K pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5660.
Abstract 2252: Predicting second breast cancers among women diagnosed with primary breast cancer using patient-level data and machine learning algorithms
Authors: Maria Eleni Syleouni, Nena Karavasiloglou, Laura Manduchi, Miriam Wanner, Dimitri Korol, Sabine Rohrmann
Journal: Cancer Research (2022)

Abstract In 2020 2.3 million women were diagnosed with breast cancer. About 7.4% of women who have been diagnosed with primary breast cancer will have a second primary breast cancer within 10 years. This study builds a prediction model for second breast cancer for women who have had primary breast cancer. Readily available cancer registry data with machine learning methods for classification are employed. The best-performing model is selected based on the area under the receiver operator curve, and the key characteristics contributing to a high risk for second breast cancer are identified based on the prediction model. Using extreme gradient boosting (XGBoost) with limited patient features we find an area under the curve of 0.65-0.70 for the testing set. Among the most important features are days from incidence to treatment, size of primary tumor based on the pathology report, and oestrogen receptor status.This research is a step towards the development of a tool that will help doctors identify women very likely to develop second breast cancer, which will prioritize their follow-up or inform their course of treatment depending on their characteristics. Citation Format: Maria Eleni Syleouni, Nena Karavasiloglou, Laura Manduchi, Miriam Wanner, Dimitri Korol, Sabine Rohrmann. Predicting second breast cancers among women diagnosed with primary breast cancer using patient-level data and machine learning algorithms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2252.
Abstract 6068: Restoring the balance between WNT and retinoic acid signaling to promote differentiation of cancer stem cells in treatment of colorectal cancer
Authors: Caroline O. Facey, Victoria O. Hunsu, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2022)

Abstract Given that the stem cell (SC) marker ALDH is a key component of the retinoic acid (RA) signaling pathway and since APC mutation leads to increased WNT signaling and overpopulation of ALDH+ SCs in colorectal cancer (CRC), we hypothesized that human CRC evolves due to an imbalance between dysregulated RA and WNT signaling. Herein, we investigated how to target the link between these two pathways to restore proper WNT and RA signaling, and promote differentiation of CSCs along the neuroendocrine cell (NEC) lineage. Accordingly, we conducted in vitro experiments to determine if restoring wt-APC in APC-mutant CRC cells reduces Wnt/β-catenin signaling, increases sensitivity to retinoids, reduces cell proliferation, reduces expression of stem cell markers, reduces the number of ALDH+ cells, and enhances NEC maturation. We utilized Nanostring profiling, TCF reporter assay, western blot, and fluorescence activated cell sorting analyses to ascertain the effects of restoring WNT in HT29 CRC cells. We found that induction of wt-APC expression decreased WNT/β-catenin signaling and reduced protein expression of WNT-target genes. Notably, inducing wt-APC decreased ATRA-induced expression of the WNT target gene CYP26A1 (by 50%), which is predicted to increase RA signaling by lowering the degradation of RA. Indeed, wt-APC increased sensitivity of CRC cells to ATRA-induced inhibition of cell proliferation in a dose-dependent manner. Expression of ALDH1A1 decreased 3-fold by ATRA treatment and inducing wt-APC furthered the decrease by an additional 2-fold. Furthermore, we found an increase in the protein expression of several NEC markers including CHGA, GLP2R, NSE (ENO2), and SSTR1, and an increased number of GLP2R+ NECs upon inducing wt-APC. Thus, the link between WNT and RA signaling at the level of CYP26A1, provides a mechanism that can explain how mutant APC leads to decreased maturation of ALDH+ SCs along the NEC lineage and an increased number of ALDH+ SCs. Therefore, discovering ways to increase differentiation of SCs along the NEC lineage in vivo might lead to new more effective treatment strategies involving retinoids for CRC patients. Citation Format: Caroline O. Facey, Victoria O. Hunsu, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman. Restoring the balance between WNT and retinoic acid signaling to promote differentiation of cancer stem cells in treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6068.
Abstract LB544: Targeting adaptive metabolic program as a novel treatment approach for TKIs-failed ALK-positive NSCLCs
Authors: You Won Lee, Hun Mi Choi, Seung Yeon Oh, Eun Ji Lee, Kyoung-Ho Pyo, Jae Hwan Kim, Youngseon Byeon, Seong Gu Heo, Sun Min Lim, Min Hee Hong, Chang Gon Kim, Hye Ryun Kim, Mi Ran Yun, Byoung Chul Cho
Journal: Cancer Research (2022)

Abstract Introduction: Acquired resistance to ALK-tyrosine kinase inhibitors (ALK-TKIs) treatment, particularly target-off resistance, remains a clinical challenge for ALK-rearranged non-small cell lung cancer (NSCLC). To explore novel vulnerabilities of ALK TKI-resistant cancer cells, we focused on their distinct metabolic pathways for growth and survival. Experimental Design: To investigate metabolic pathways in resistance mechanisms, we generated ALK-TKIs -acquired-resistant in vitro/vivo models. We screened metabolite mechanisms using metabolite assay kit, Seahorse Extracellular Flux Analyzer, real-time PCR, western blot, RNA-seq in resistant models. Results: Through an integrated transcriptomic and metabolic assay screening approach, we identified the enhanced reliance on glutamine metabolism in target-off ALK-TKIs-resistant cells. Specifically, resistant cells were characterized by upregulation of glutaminase 1 (GLS1), a mitochondrial enzyme hydrolyzing glutamine into glutamate, simultaneously with downregulation of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this metabolic state intensively accelerates glutaminolysis and subsequent mitochondrial glutamine-derived aspartate synthesis, resulting in TKI resistance by reinforcing antioxidant capacity with increase of NADPH and glutathione. Mechanistically, GLS1 inhibition elicited a marked reduction of cell growth with increase of reactive oxygen species (ROS) in resistant cells, which was restored by supplementation of exogenous aspartate. The antitumor activity of GLS1 inhibition against resistant tumor cells was further validated in in vivo experiments, patient-derived xenograft (PDX) and EML4-ALK transgenic mice. More importantly, glutaminase inhibitor CB-839 enhanced the therapeutic efficacy of anti-PD-L1 treatment in immune checkpoint blockade (ICB)-resistant EML4-ALK transgenic mice. Conclusion: Our findings highlight a new metabolic vulnerability of ALK-TKIs resistant tumors and provide a rationale for targeting GLS1 as a potential treatment option to overcome ALK-TKIs resistance. Citation Format: You Won Lee, Hun Mi Choi, Seung Yeon Oh, Eun Ji Lee, Kyoung-Ho Pyo, Jae Hwan Kim, Youngseon Byeon, Seong Gu Heo, Sun Min Lim, Min Hee Hong, Chang Gon Kim, Hye Ryun Kim, Mi Ran Yun, Byoung Chul Cho. Targeting adaptive metabolic program as a novel treatment approach for TKIs-failed ALK-positive NSCLCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB544.